Cellular Basis of Behavioral Circadian Rhythms in Mammals: The Role of Neuromedin S (Nms)-Producing Cells in the Suprachiasmatic Nucleus

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Behavioral circadian rhythms in mammals are controlled by highly heterogeneous populations of neurons located in the suprachiasmatic nucleus (SCN). Lesion and transplantation studies have established that the SCN is both necessary and sufficient for the generation of daily rhythms in locomotion. It remains uncertain, however, whether this pacemaking property of the SCN is limited to certain subsets of cells or intrinsic to all neurons within the SCN. To dissect out the cellular properties of circadian rhythms, we utilized a BAC transgenic mouse line in which Cre recombinase (iCre) is driven by the promoter of neuromedin S (Nms), a neuropeptide that has restricted expression in ~40% of cells within the SCN. Using this cell-type specific driver, we genetically altered the molecular oscillation of Nms-positive cells by overexpressing the ClockΔ19 or the Period2 transgene. ClockΔ19 is a semi-dominant mutation that leads to lengthened behavioral circadian periods when expressed in the majority of SCN cells. Likewise, Period2, when overexpressed in all or almost all of the SCN neurons, lead to the loss of behavioral circadian rhythms. We found that, intriguingly, the transgenic expression of ClockΔ19 only in Nms-positive neurons leads to a lengthened period in circadian rhythms while the overexpression of Per2 in Nms-expressing neurons causes the loss of daily rhythms altogether, suggesting that behavioral rhythms can be controlled by the molecular oscillation of Nms-positive cells. Next, to ascertain whether Nms-expressing neurons are required for normal behavioral circadian rhythms, we utilized a tetanus toxin-based technology that permits the inducible and reversible inhibition of neurotransmission. Surprisingly, this genetic manipulation revealed that synaptic neurotransmission from Nms neurons is essential for the generation of behavioral circadian rhythms. Taken together, these results indicate that Nms marks a specialized subgroup of neurons that is both necessary and sufficient for the production of circadian rhythms in behavior.

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